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Pediatric diarrheal diseases: A public health issue that requires further standardization
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As the second leading cause of death worldwide among children aged younger than 5 years, gastroenteritis poses a serious burden, both globally and domestically.
On a global scale, gastroenteritis causes more than 700,000 deaths annually among children aged younger than 5 years, Stephen B. Freedman, MDCM, MSc, associate professor of pediatrics at Alberta Children’s Hospital Research Institute at the University of Calgary in Alberta, Canada, told Infectious Diseases in Children. Domestically, very few children die from diarrheal diseases, but they are still a major cause of morbidity and mortality. Acute gastroenteritis is present among approximately 179 million people in the United States, resulting in approximately 128,000 hospitalizations, David Schnadower, MD, MPH, assistant professor of pediatrics at Washington University in St. Louis, told Infectious Diseases in Children. There have been an estimated 1.7 million pediatric ED visits for gastroenteritis.
The burden of diarrheal diseases goes beyond morbidity and mortality. When children are sick with diarrhea, they often miss school, which leads to caregivers staying home from work. “There are significant economic implications of children not being able to attend school,” Freedman, who is an associate professor in the department of pediatrics, sections of Emergency Medicine and Gastroenterology at Alberta Children’s Hospital Research Institute, said. “Caregivers stay home from work, which has an overall impact on the productivity of society as a whole.”
With an estimated 50% household transmission rate, according to Schnadower, parents and caregivers are significantly more susceptible to illness, further increasing their odds of missing work.
Stephen B. Freedman, MDCM, MSc, associate professor in the department of pediatrics, sections of Emergency Medicine and Gastroenterology at Alberta Children’s Hospital Research Institute, said the burden of diarrheal diseases goes beyond morbidity and mortality.
Herperger L; reprinted with permission
Fortunately, recent progress has been made in the management and treatment of diarrheal diseases.
“Management of diarrheal diseases has undergone radical improvement with the use of oral rehydration formulas both in the United States and internationally. Deaths from acute gastroenteritis have decreased with the use of oral rehydration,” Janet A. Englund, MD, professor of pediatric infectious diseases at the University of Washington and Seattle Children’s Hospital, told Infectious Diseases in Children.
Still, more work needs to be done, according to Andi L. Shane, MD, MPH, MSc, associate professor in the Division of Infectious Disease, Department of Pediatrics at Emory University School of Medicine in Atlanta. “Although we have made progress in reducing the burden of diarrhea, infants and children from resource-challenged settings, children who have received antimicrobial agents, and those with immunocompromising conditions continue to experience enteric infections. Most are attributed to viral infections or are of unknown etiology. In the United States, noroviruses are the most common causes of outbreaks of diarrhea,” Shane told Infectious Diseases in Children.
Viral, bacterial causes
Viral diarrheal diseases, most notably rotavirus and norovirus, are most common among children in the United States, according to Robert W. Frenck Jr., MD, medical director of the division of infectious diseases at Cincinnati Children’s Hospital Medical Center.
Before the introduction of a vaccine in 2006 and 2008, rotavirus was the leading cause of diarrhea among infants and young children in the US, Shane said. During that time, most children experienced rotavirus before their fifth birthday, according to CDC data.
Norovirus causes 19 million to 21 million cases of acute gastroenteritis annually among all age groups, leading to 1.7 million to 1.9 million outpatient visits and 400,000 ED visits in the US, primarily among young children, according to the CDC. Approximately 56,000 to 71,000 hospitalizations and 570 to 800 deaths, mostly among young children and the elderly, are caused by norovirus each year.
Bacterial infections account for a significant amount of diarrheal diseases, as well. Using data from the Foodborne Diseases Active Surveillance Network (FoodNet), Elaine Scallan, PhD, assistant professor at the Colorado School of Public Health, University of Colorado Denver, and colleagues found that Campylobacter, Escherichia coli O157, nontyphoidal Salmonella, Shigella, and Yersinia enterocolitica caused an estimated 291,162 illnesses, resulting in 102,746 physician visits, 7,830 hospitalizations and 64 deaths annually among children aged younger than 5 years.
Robert Frenck
“Surveillance data are really just the tip of the iceberg,” Scallan told Infectious Diseases in Children. For an illness to be included in FoodNet surveillance, the ill person must seek medical care and a stool sample must be submitted, and a clinical laboratory must test for and identify the causative agent. So, many cases of gastroenteritis are not represented in data from FoodNet.
For every laboratory-confirmed case of E. coli O157, Campylobacter, nontyphodial Salmonella and Shigella, there are between 26 and 33 illnesses that are not laboratory-confirmed, according to FoodNet estimates.
Changing epidemiology of diarrheal diseases
Rotavirus vaccines have changed the epidemiology of diarrheal diseases in the United States, Frenck told Infectious Diseases in Children.
Before the vaccines, rotavirus contributed to more than 400,000 physicians’ visits, 200,000 ED visits, 55,000 to 70,000 hospitalizations and 20 to 60 deaths each year among children aged younger than 5 years, according to data from the CDC.
“Rotavirus disease has since decreased significantly in the United States,” Shane said.
Efficacy studies have shown that rotavirus vaccines, RotaTeq (Merck) and Rotarix (GlaxoSmithKline), are 85% to 98% protective against severe rotavirus disease, the CDC reports. During the first year after vaccination, rotavirus vaccines are 74% to 87% protective against rotavirus disease of any severity, according to CDC data.
In addition to direct protection among children who receive the vaccine, children and adults benefit from indirect protection, as immunized children are significantly less likely to transmit rotavirus. The vaccine’s effect on the epidemiology of rotavirus is clear, as “the winter and early spring seasonality of rotavirus seen in the pre-vaccine era has dissipated,” Shane said.
As diarrheal diseases caused by rotavirus become less common, other diarrheal diseases appear more prominent.
“Norovirus is now the leading cause of diarrheal diseases in the United States,” Frenck said.
This does not necessarily mean, however, there has been an increase in norovirus diseases, according to Freedman.
Janet Englund
“We are better able to detect viruses now. We’ve been able to identify rotavirus for many years now. Up until the past 5 years or so, other viruses, like norovirus, have been extremely challenging to identify,” he said. “Now we can use molecular-based methods to identify norovirus and other viral diarrheal diseases, so we are able to identify the many other causes, whereas previously we could not.”
Each year, rotavirus vaccines prevent an estimated 40,000 to 50,000 hospitalizations among infants and young children in the United States, according to Shane. However, Schnadower said there has not been a significant change in the number of young children presenting to the ED with diarrheal diseases since the vaccines were introduced in 2006.
“Based on surveys conducted at large children’s hospitals, the burden of ED diarrheal diseases has not significantly decreased,” he said. “We are probably seeing viral diarrhea other than rotavirus.”
The next step is to apply the method that has worked so well for rotavirus to norovirus, according to Englund. “We need an approach to prevent norovirus disease, which is now as common as rotavirus was. To see a rotavirus-like decrease among noroviruses, we need a vaccine. Vaccine development is under way.”
The importance of ticking the right boxes
Another issue that requires further improvement is the management of bloody diarrhea, which is an indicator of the sometimes lethal E. coli O157.
“E. coli O157 creates toxin that can lead to renal failure,” Schnadower said. “It is one of the main causes of renal failure among children in developed countries. Management of these children is still problematic.”
Research shows that when E. coli O157 is properly managed, particularly with aggressive hydration therapy, anuric renal failure may be prevented, according to Schnadower. But when the severity of bloody diarrhea and the possibility of E. coli O157 is not recognized, patients are identified too late; they may develop renal failure and require dialysis or, in some cases, a kidney transplant.
Although guidelines state that stool cultures should be ordered for all cases of bloody diarrhea, not all patients who report blood in their stool are asked to submit a stool sample, according to Scallan and colleagues. This discrepancy may be due to the idea that the blood is hemorrhoidal or from a tear.
Data from FoodNet indicate 96% of physicians stated they would order a stool culture for a child with bloody diarrhea. Conversely, a review of ED and urgent care records from a Texas children’s hospital, cited by Scallan and colleagues, found that stool cultures were ordered for only 44% of children who received a diagnosis for acute diarrheal illness with bloody diarrhea.
Elaine Scallan
Scallan echoed these findings during an interview with Infectious Diseases in Children. “If you ask physicians, they will say, ‘Yes, I’ll definitely test if a patient has bloody diarrhea.’ But when you ask patients with bloody diarrhea if they’ve been tested, there is a lower proportion who report being tested,” she said.
The lack of routine testing for E. coli O157 is concerning because early treatment may decrease the risk for complications. Sometimes, even if a patient submits a stool sample, the laboratory may not specifically test the sample for E. coli O157.
The CDC recommends all stool samples from patients with community-acquired diarrhea that are submitted to clinical laboratories for routine testing be tested for E. coli O157 regardless of age, season or absence of blood in the stool, according to Scallan and colleagues.
“If the physician doesn’t tick the right boxes, E. coli O157 may not be automatically tested for,” she said. “However, the proportion of labs routinely testing for E. coli O157 has been increasing overtime.”
Moving forward, the current guidelines on management of bloody diarrhea require reinforcement so adherence increases. Severe and sometimes deadly complications can be avoided by simply testing for E. coli O157.
Treatment varies
There is significant variation in treatment of diarrheal diseases among children, further indicating a need for well-evidenced, standardized guidance.
“Some children will be given IV fluids when oral fluids would suffice. There are children who are not properly given antiemetics; some are not given antiemetics when necessary, and others receive them when unnecessary,” Schnadower said.
Frenck discussed the simplicity of oral rehydration and how it is underused in developed countries such as the United States.
“Practices may have changed since I was in general pediatrics, but oral rehydration was not used as well as it could be,” he said. “This is partly because the proper instructions for use of oral rehydration solutions (ORS) are not well known. Many patients or caregivers don’t know ORS should be consumed slowly. Naturally, a dehydrated child will want to quickly drink as much ORS as they can. But large amounts of liquid will further upset an upset stomach. If ORS is given slowly and progressively, you can typically rehydrate children as much as 5%.”
There is a tremendous luxury of living in the United States, according to Frenck. Access to medical care opens patients up to treatment options that are unavailable in underdeveloped countries. ORS may be one of the only options for treating diarrheal diseases in underdeveloped areas, and its simplicity and cost-effectiveness is underrated in the United States.
“Because of this, ORS hasn’t been pushed as much in the United States. IV hydration works well but is not necessary in many cases. In some respects, IV rehydration is faster and easier than if you are administering a tablespoon of liquid every 5 or 10 minutes, as with oral rehydration,” Frenck said.
A quick solution is certainly the draw of IV rehydration.
“On a global scale, the majority of children with diarrheal diseases do not need aggressive medical intervention. These children simply require time,” Freedman said. “There needs to be teaching and acceptance that oral rehydration can and will work if done properly. The challenge is that parents want medical intervention. The biggest challenge is that there is no magic bullet that makes diarrheal diseases go away and makes the child feel better.”
Probiotics may be another simple, cost-effective treatment for diarrheal diseases. Research and evaluation of the role of probiotics within gastroenteritis treatment are currently under way, but some existing study data indicate they may be a viable treatment option.
“Probiotics may treat diarrhea, fever and vomiting faster so parents can worry less and not feel the need to seek medical care,” according to Freedman.
When administered in appropriate amounts, probiotics offer a health benefit to the host. These beneficial bacteria protect the host from harmful or pathogenic microbes and promote mucosal immunity, thereby helping to maintain a strong, healthy environment in the gut.
“Probiotics, including bifidobacteria and lactobacilli, have been associated with protective immune responses and have shown to decrease stool frequency and days of diarrhea,” according to Shane.
The effects of probiotics are most pronounced with viral diarrhea, especially rotavirus, she said. Probiotics appear to have the greatest benefits when used for prevention of diarrhea rather than treatment after onset of symptoms representing disruption of the microbiota have occurred.
The benefits may seem insignificant in a resource-endowed setting, as a reduction of 1 to 2 days of diarrhea may not be comparable to the effect of other diarrheal disease interventions. However, probiotics are commercially available in many forms, as foods or dietary supplements, making them easily accessible and inexpensive.
Due to the infectious nature of diarrheal diseases, inexpensive, preventive treatment options that are available to everyone are valuable, as all members of society, from patients to health care systems, may benefit from the prevention of these diseases.
Looking to the future: IDSA guidelines
There is still much work to be done regarding the treatment and prevention of diarrheal diseases, as indicated by the significant number of Americans affected by diarrheal diseases.
IDSA is set to publish guidelines on the management of infectious diarrhea in early 2015. The guidelines have an opportunity to highlight significant issues regarding diarrheal diseases that are not presently well known or regarded, as well as reinforce a standard of care when treating diarrheal diseases, according to experts.
Most importantly, management guidelines should be established by those most involved with managing diarrheal diseases.
“Guidelines on the management of diarrheal diseases should be produced with significant input from frontline care providers — family physicians, pediatricians, ED physicians — so that the guidelines highlight the issues they deal with on a regular basis, with obvious expert input from other groups, as appropriate. Management guidelines should focus on day-to-day practice,” Freedman said.
Schnadower would like to see guidelines with recommendations that have strong evidence behind them.
The effectiveness of oral rehydration and how to use it appropriately is something Frenck and Freedman would like the upcoming guidelines to reinforce.
In addition, Frenck hopes the guidelines discuss the appropriate use of antibiotics when treating diarrheal diseases. “The majority of diarrhea is caused by a virus, or parasites, and is not bacterial, so the use of antibiotics to treat diarrheal diseases is rare. However, when bacteria are detected, antibiotics may be helpful, especially if it’s a second case in the same household,” Frenck said.
The importance of testing stool samples for E. coli O157 is another issue the guidelines could address. Although the existing guidelines recommend obtaining a stool sample from patients with bloody diarrhea, testing for E. coli O157 is not standard practice.
“Guidelines should focus on standardizing care, focusing on the use of oral rehydration therapy, minimizing diagnostic investigation and appropriate use of co-intervention such as ondansetron and probiotics. They should have a clear take-home message for physicians on how to manage diarrheal diseases,” Freedman said.
It is clear the management, treatment and prevention of diarrheal diseases is in need of standardization. Illnesses that affect the majority of the population on various levels of severity would benefit from inexpensive, widely available treatment and prevention solutions, according to experts. Upcoming guidance has the ability to highlight these solutions – by Amanda Oldt
References:
Scallan E. Pediatr Infect Dis J. 2013;32:217–221.
For more information:
Janet A. Englund, MD, can be reached at 4800 Sand Point Way NE, Seattle, WA 98105.
Stephen B. Freedman, MDCM, MSc, can be reached at 2888 Shaganappi Trail NW, Calgary, Alberta T3B 6A8; email: stephen.freedman@albertahealthservices.ca.
Robert W. Frenck Jr., MD, can be reached at 3333 Burnet Avenue, Cincinnati, OH 45229-3026; email: robert.frenck@cchmc.org.
Elaine Scallan, PhD, can be reached at 13001 E. 17th Place, B119 Bldg, Aurora, CO 80045; email: elaine.scallan@ucdenver.edu.
David Schnadower, MD, MPH, can be reached at One Children’s Place, St. Louis, MO 63110.
Andi L. Shane, MD, MPH, MSc, can be reached at 2015 Uppergate Road, Atlanta, GA 30322; email: ashane@emory.edu.
Disclosure: Englund reports financial ties with GlaxoSmithKline. Infectious Diseases in Children was unable to confirm financial disclosures for Schnadower at the time of publication.Shane reports financial ties with BioGaia. Freedman, Frenck, and Scallan report no relevant financial disclosures.
Perspective
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James E. Colletti, MD
Growing body of evidence supports single-dose therapy.
Vomiting is a presenting feature of pediatric acute gastroenteritis. Oral rehydration is the cornerstone of therapy for acute gastroenteritis, and continued vomiting is a significant barrier to successful rehydration. Historically, use of an antiemetic in pediatric acute gastroenteritis has been discouraged secondary to adverse reactions. Almost 20 years ago, the AAP published practice guidelines discouraging the use of antiemetics in children younger than 5 years of age. This AAP guideline was based on adverse reactions associated with antiemetic administration such as extrapyramidal side effects, apnea and central nervous system depression. It is important to note that the aforementioned concerns occurred with phenothiazine antiemetics, before serotonin type 3 (5-hydroxytryptaimine3, 5-HT3) receptor antagonists were widely employed.
Serotonin type-3 receptor antagonists, such as ondansetron, have been shown to be effective antiemetic therapies in children receiving chemotherapy, as well as in those with postsurgical-induced emesis. Multiple researchers have looked at the efficacy and safety of ondansetron in patients with acute gastroenteritis and found ondansetron to be effective in decreasing the episodes of emesis during oral rehydration, ED length of stay and hospital admission rates. Children with acute gastroenteritis treated with ondansetron have been found less likely to vomit, vomited less frequently, had an increase in oral intake, and were less likely to require parental hydration.
In summary, there is growing body of evidence that administration of single-dose ondansetron is an effective and viable therapy to facilitate oral rehydration in pediatric acute gastroenteritis.Perspective
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Yaron Finkelstein, MD
Efficacy of single-dose ondansetron is proven.
The efficacy of single-dose ondansetron as an antiemetic in children with acute gastroenteritis has been proven in several clinical trials, with significant improvements in various clinical outcomes, such as increased oral fluid intake and reduction in need for IV rehydration. In the real-world, between 1995 and 2009, ondansetron administration in US EDs increased dramatically — more than 330-fold — from 38,000 to 12.6 million doses per year. Pediatric usage has also increased, with over two million doses administered to children in US EDs each year, almost 85% via the oral route.Recent FDA warnings regarding a possible link between ondansetron and cardiac arrhythmias have been a source of uncertainty and confusion for practicing clinicians. Specifically, in September 2011 the FDA issued a warning that ondansetron may induce fatal arrhythmias. In June 2012, the FDA issued an update linking the risk of QT-prolongation to the administration of a 32-mg IV dose. However, the screening recommendations remained unchanged and suggest an electrocardiogram and serum electrolyte testing to virtually all patients before administration of ondansetron, in any dose or route. These non-targeted recommendations have potential harm, including withholding an effective treatment, discomfort and delayed care, and may lead to additional unnecessary investigations and anxiety. A recent in-depth post-marketing study analyzed all relevant published and grey literature reports, as well as investigated adverse drug reaction reports catalogued in the FDA Adverse Events Reporting System, the WHO pharmacovigilance system Vigibase, and the manufacturer’s registry. With hundreds of millions of administered doses globally in over 23 years, there has not been a single report of an arrhythmia occurring in an otherwise healthy child (or adult) receiving a single oral dose of ondansetron. Moreover, pharmacokinetic data on a single oral dose (ie, low bioavailability and low maximal serum concentration) make such an event very improbable and explain the lack of any documented cases.
In summary, available data provide strong evidence that single-dose ondansetron is both an effective and safe antiemetic in children with acute gastroenteritis and no known cardiac risk factors.Click Here to Manage Email Alerts